Drinking induced by subcutaneous injection of angiotensin II in the rat is blocked by the selective AT1 receptor antagonist DuP 753 but not by the selective AT2 receptor antagonist WL 19

Abstract Adrenal steroidogenesis is modulated by humoral and neuronal factors and blood flow. Angiotensin II (AII) stimulates adrenal cortical aldosterone and cortisol production and medullary catecholamine release. However, AII regulation of adrenal vascular tone has not been characterized. We examined the effect of AII on diameters of cannulated bovine adrenal cortical arteries. Cortical arteries (average internal diameter = 230 μm) were constricted with U46619 and concentration-diameter responses to AII (10−13 to 10−8 mol/liter) were measured. In endothelium-intact arteries, AII induced dilations at low concentrations (maximum dilation = 25 ± 6% at 10−10 mol/liter) and constrictions at high concentrations (maximum constriction = 25 ± 18% at 10−8 mol/liter). AII constrictions were blocked by the angiotensin type 1 (AT1) receptor antagonist, losartan (10−6 mol/liter). AII dilations were enhanced by losartan (maximal dilation = 48 ± 8%), abolished by endothelial cell removal or N-nitro-l-arginine (L-NA, 3 × 10−5 mol/liter) and inhibited by the angiotensin type 2 (AT2) receptor antagonist, PD123319 (10−6 mol/liter, maximal dilation = 18 ± 4%). In a 4,5-diaminofluorescein diacetate nitric oxide (NO) assay of isolated cortical arteries, AII stimulated NO production, which was abolished by PD123319, L-NA, or endothelial cell removal. Western immunoblot of arterial homogenates and endothelial and zona glomerulosa cell lysates revealed 48-kD and 50-kD bands corresponding to AT1 and AT2 receptors, respectively, in all three and a 140-kD band corresponding to endothelial NO synthase in endothelial cells and arteries. Our results demonstrate that AII stimulates adrenal cortical arterial dilation through endothelial cell AT2 receptor activation and NO release and AT1 receptor-dependent constriction.

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Characterisation of angiotensin II receptors in isolated human subcutaneous resistance arteries

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/14703203010020010601 ◽

2001 ◽

Vol 2 (1_suppl) ◽

pp. S37-S41 ◽

Cited By ~ 2

Author(s):

Hoa Ytterberg ◽

Lars Edvinsson

Keyword(s):

Angiotensin Ii ◽

Receptor Antagonist ◽

At1 Receptor ◽

Receptor Subtypes ◽

At2 Receptor ◽

Ang Ii ◽

Resistance Arteries ◽

Receptor Antagonists ◽

Response Curves ◽

At1 Receptor Antagonists

Subcutaneous arteries have been used as a model for resistance arteries, which are potentially involved in enhanced blood pressure (BP) regulation in man. Angiotensin II (Ang II) is an important regulator of tone, acting via type 1 (AT1-) and type 2 (AT2-) receptor subtypes. The aim of this study was to characterise the Ang II receptors in isolated human subcutaneous arteries, using pharmacological and molecular methods. Subcutaneous arteries were obtained from patients undergoing elective gut surgery and were carefully dissected from the abdominal wall. Cylindrical segments were mounted on two L-shaped metal prongs, one of which was connected to a force-displacement transducer for continuous recording of isometric tension. Concentration-response curves to Ang II were constructed in the presence and absence of various selective AT1-receptor antagonists, candesartan, EXP3174, irbesartan and losartan, and the AT2-receptor antagonist, PD 123319. Responses to Ang II were measured as increases in force (mN) and expressed as a percentage of the response to 60 mM of KCl. Ang II caused a concentration-dependent contraction (pEC50=9.45±0.48, Emax=120±13%). Candesartan and EXP3174 caused concentration-dependent depression of the Emax of Ang II without any major shift of pEC50. Losartan and irbesartan caused a significant, dose-dependent rightward shift of the Ang II contraction-response curve in human subcutaneous arteries. The results show that contractile responses of human subcutaneous arteries are mediated via the AT1-receptor. The AT1-receptor antagonists, candesartan and EXP3174, acted in an insurmountable manner, while losartan and irbesartan were surmountable AT1-receptor antagonists. The AT2-receptor antagonist, PD 123319, (10, 100 nM) had no effect on Ang II-induced contraction. This is supported by the positive identification of mRNA for the human AT 1-receptor by RT-PCR.

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Inhibition of the haemodynamic effects of angiotensin II in conscious rats by AT2-receptor antagonists given after the AT1-receptor antagonist, EXP 3174

British Journal of Pharmacology ◽

10.1111/j.1476-5381.1992.tb14540.x ◽

1992 ◽

Vol 107 (3) ◽

pp. 873-880 ◽

Cited By ~ 30

Author(s):

R.E. Widdop ◽

S.M. Gardiner ◽

P.A. Kemp ◽

T. Bennett

Keyword(s):

Angiotensin Ii ◽

Receptor Antagonist ◽

At1 Receptor ◽

Haemodynamic Effects ◽

At2 Receptor ◽

Receptor Antagonists ◽

Conscious Rats

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Pharmacology of XR510, a Potent Orally Active Nonpeptide Angiotensin II AT1 Receptor Antagonist with High Affinity for the AT2 Receptor Subtype

Journal of Cardiovascular Pharmacology ◽

10.1097/00005344-199509000-00003 ◽

1995 ◽

Vol 26 (3) ◽

pp. 354-362 ◽

Cited By ~ 12

Author(s):

Pancras C. Wong ◽

Mimi L. Quan ◽

JoAnne M. Saye ◽

Roberta Bernard ◽

Earl J. Crain ◽

...

Keyword(s):

Angiotensin Ii ◽

Receptor Antagonist ◽

At1 Receptor ◽

Receptor Subtype ◽

At2 Receptor ◽

High Affinity ◽

Orally Active

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Angiotensin II type 1 receptor blockade restores angiotensin-(1–7)-induced coronary vasodilation in hypertrophic rat hearts

Clinical Science ◽

10.1042/cs20120519 ◽

2013 ◽

Vol 125 (9) ◽

pp. 449-459 ◽

Cited By ~ 31

Author(s):

Álvaro P. S. Souza ◽

Deny B. S. Sobrinho ◽

Jônathas F. Q. Almeida ◽

Gisele M. M. Alves ◽

Larissa M. Macedo ◽

...

Keyword(s):

Angiotensin Ii ◽

Receptor Antagonist ◽

At1 Receptor ◽

At2 Receptor ◽

Receptor Blockade ◽

Coronary Vasodilation ◽

Mas Receptor ◽

Rat Hearts ◽

Pre Treatment

The aim of the present study was to investigate the coronary effects of Ang-(1–7) [angiotensin-(1–7)] in hypertrophic rat hearts. Heart hypertrophy was induced by abdominal aorta CoA (coarctation). Ang-(1–7) and AVE 0991, a non-peptide Mas-receptor agonist, at picomolar concentration, induced a significant vasodilation in hearts from sham-operated rats. These effects were blocked by the Mas receptor antagonist A-779. Pre-treatment with L-NAME (NG-nitro-L-arginine methyl ester) or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one) [NOS (NO synthase) and soluble guanylate cyclase inhibitors respectively] also abolished the effect of Ang-(1–7) in control hearts. The coronary vasodilation produced by Ang-(1–7) and AVE 0991 was completely blunted in hypertrophic hearts. Chronic oral administration of losartan in CoA rats restored the coronary vasodilation effect of Ang-(1–7). This effect was blocked by A-779 and AT2 receptor (angiotensin II type 2 receptor) antagonist PD123319. Acute pre-incubation with losartan also restored the Ang-(1–7)-induced, but not BK (bradykinin)-induced, coronary vasodilation in hypertrophic hearts. This effect was inhibited by A-779, PD123319 and L-NAME. Chronic treatment with losartan did not change the protein expression of Mas and AT2 receptor and ACE (angiotensin-converting enzyme) and ACE2 in coronary arteries from CoA rats, but induced a slight increase in AT2 receptor in aorta of these animals. Ang-(1–7)-induced relaxation in aortas from sham-operated rats was absent in aortas from CoA rats. In vitro pre-treatment with losartan restored the Ang-(1–7)-induced relaxation in aortic rings of CoA rats, which was blocked by the Mas antagonist A-779 and L-NAME. These data demonstrate that Mas is strongly involved in coronary vasodilation and that AT1 receptor (angiotensin II type 1 receptor) blockade potentiates the vasodilatory effects of Ang-(1–7) in the coronary beds of pressure-overloaded rat hearts through NO-related AT2- and Mas-receptor-dependent mechanisms. These data suggest the association of Ang-(1–7) and AT1 receptor antagonists as a potential therapeutic avenue for coronary artery diseases.

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